A systematic investigation of the NMR relaxation properties of Fe(iii)-EDTA derivatives and their potential as MRI contrast agents

We report a detailed investigation of the potential of Fe(iii) complexes with H(4)EDTA derivatives containing different spacers as magnetic resonance imaging (MRI) contrast agents: trans-cyclohexane-1,2-diamine (t-H(4)CDTA), cis-cyclohexane-1,2-diamine (c-H(4)CDTA), propane-1,3-diamine (H(4)PDTA), benzene-1,2-diamine (H(4)PhDTA), trans-cyclopentane-1,2-diamine (H(4)CpDTA) and trans-cyclobutane-1,3-diamine (H(4)CBuDTA). The Fe(iii) complex of the related hexadentate ligand H(2)CBuDEDPA (6,6 '-(((trans-cyclobutane-1,3-diyl)bis(azanediyl))bis(methylene))dipicolinic acid) is also reported for comparative purposes. The X-ray structure of [Fe(1,3-CBuDEDPA)](PF6)center dot H2O evidences the six-coordination of the ligand to the metal ion and displays a distorted octahedral polyhedron. All complexes show reversible or quasi-reversible cyclic voltammograms in aqueous 0.15 M NaCl due to the Fe(iii)/Fe(ii) pair, with E-1/2 values in the range of +97 to 136 mV (vs. NHE) for the complexes with t-H(4)CDTA, c-H(4)CDTA, H(4)PhDTA and H(4)CpDTA. The longer spacers of H(4)PDTA and H(4)CBuDTA induce a stabilization of the Fe(ii) complex (E-1/2 = 260 and 294 mV vs. NHE, respectively). The Fe(iii) complexes of H(4)PDTA and H(4)CBuDTA do not contain inner-sphere water molecules. Thus, their H-1 nuclear magnetic relaxation dispersion (NMRD) profiles were analysed using an outer-sphere model. The complexes of c-H(4)CDTA and H(4)PhDTA display relaxivities that indicate the presence of a water molecule coordinated to the metal ion. A set of O-17 NMR transverse relaxation rates and chemical shifts obtained at different temperatures provided information on the water exchange kinetics. Subsequently, the analysis of the H-1 NMRD profiles provided information on the rotational dynamics of the complexes and electronic relaxation. The integrated approach reported here includes a computational DFT and CASSCF study and provides insights into the structural and dynamic parameters affecting the efficiency of these complexes as MRI contrast agents.